Cannabis sativa (CB) is the most widely used illicit substance in the United States, with lifetime prevalence of CB abuse or dependence of about 8.5%, and of any use of 32%. The principal psychoactive ingredient of CB is delta-9-tetrahydrocannabinol (THC) which acts as a ligand for widely distributed CB1 receptors in the human brain. CB use is associated with a spectrum of cognitive deficits, and epidemiological evidence has accumulated that CB use is a risk factor for psychosis. Animal studies suggest that cannabis has pervasive effects on neural function and plasticity, especially during development, which can persist after the period of exposure. Nevertheless, there is little understanding of how CB1 use affects human brain structural and functional connectivity, or whether such changes persist after discontinuation of use. This project will evaluate functional and structural connectivity and network properties in current CB users, past users (> one year abstinence) and healthy adolescents and young adults with no history of CB use (N = 30 in each group). Diffusion tensor imaging and white matter fiber tractography will be used to quantify the white matter connectivity in the whole brain. Functional MRI will be used to evaluate resting connectivity. To investigate the topological properties of the whole-brain network, graph theoretic analysis will be used to measure global and regional network properties. Preliminary data indicated CB users have alterations in global network organization, and that these abnormalities are associated with increased impulsivity, increased schizotypy and impaired verbal function. We predict that CB use is associated with poorer efficiency in network organization for both structure and function, particularly in regions with high densities of CB1 receptors. It is predicted that current CB users will show greater alterations in connectivity than abstinent users, and that earlier onset and more exposures to CB will predict greater severity of connectivity disturbance. In current and former CB1 users, we predict that severity of network alterations will correlate with cognitive measures and personality traits associated with CB use. This approach may lead to insights into how CB use affects the human brain network; whether network disturbances recover after cessation of use; and the relationship of network alterations to personality and cognitive function. More generally, since drugs of abuse often cause widely distributed changes in motivational and cognitive systems within the brain, the methods developed in this study may have broad application in the study of the effects of drug use and response to interventions.